title: Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses.
abstract: Formyl-peptide receptor type 2 (FPR2), also called ALX (the lipoxin A4 receptor), conveys the proresolving properties of lipoxin A4 and annexin A1 (AnxA1) and the proinflammatory signals elicited by serum amyloid protein A and cathelicidins, among others. We tested here the hypothesis that ALX might exist as homo- or heterodimer with FPR1 or FPR3 (the two other family members) and operate in a ligand-biased fashion. Coimmunoprecipitation and bioluminescence resonance energy transfer assays with transfected HEK293 cells revealed constitutive dimerization of the receptors; significantly, AnxA1, but not serum amyloid protein A, could activate ALX homodimers. A p38/MAPK-activated protein kinase/heat shock protein 27 signaling signature was unveiled after AnxA1 application, leading to generation of IL-10, as measured in vitro (in primary monocytes) and in vivo (after i.p. injection in the mouse). The latter response was absent in mice lacking the ALX ortholog. Using a similar approach, ALX/FPR1 heterodimerization evoked using the panagonist peptide Ac2-26, identified a JNK-mediated proapoptotic path that was confirmed in primary neutrophils. These findings provide a molecular mechanism that accounts for the dual nature of ALX and indicate that agonist binding and dimerization state contribute to the conformational landscape of FPRs.
authors.affiliation: William Harvey Research Institute, Barts and The London School of Medicine, London EC1M 6BQ, United Kingdom.
authors.forename: Sadani N
authors.initials: SN
authors.lastname: Cooray
authors.forename: Thomas
authors.initials: T
authors.lastname: Gobbetti
authors.forename: Trinidad
authors.initials: T
authors.lastname: Montero-Melendez
authors.forename: Simon
authors.initials: S
authors.lastname: McArthur
authors.forename: Dawn
authors.initials: D
authors.lastname: Thompson
authors.forename: Adrian J L
authors.initials: AJ
authors.lastname: Clark
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Flower
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D060807:Bioluminescence Resonance Energy Transfer Techniques; D019281:Dimerization; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D044042:Receptors, Formyl Peptide / Q000737:chemistry* / Q000378:metabolism*; D000685:Serum Amyloid A Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017305:Annexin A1; D044042:Receptors, Formyl Peptide; D000685:Serum Amyloid A Protein; C481578:formyl peptide receptor 2, mouse; D016753:Interleukin-10
keywords: inflammation; leukocyte; resolution signaling